The present invention relates to novel macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to a novel class of 4xe2x80x2-substituted 16-membered macrolides, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
Macrolide antibiotics play a therapeutically important role, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and to the number and nature (neutral or basic) of the sugars. Macrolides are classified according to the size of the lactone ring (12, 14, 15 or 16 atoms). The macrolide antibiotic families (14-, 15- and 16-membered ring derivatives) exhibit a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin and josamycin.
The 16-membered ring macrolide antibiotics constitute an important clinically useful series of naturally occurring compounds within the macrolide class of antibiotics, as they show some advantages over 14-membered ring compounds (gastrointestinal tolerance and activity against strains expressing resistance of the inducible type). Sixteen membered macrolides usually contain an amino-disaccharide-4-O-(L-mycarosyl)-D-mycaminose and/or D-desosamine. One class has only neutral sugars. The sixteen membered macrolides can be classified into two major groupsxe2x80x94the leucomycins and the tylosin series.
The tylosin series is divided into two groupsxe2x80x94IIA and IIBxe2x80x94which differ at the C-6-side chain and the nature of the sugars on the chromophore. Tylosin consists of a substituted 16-membered ring lactone (tylonolide), an aminosugar (D-mycaminose) attached to C-5, two neutral sugars (D-mycinose attached at C-23 and L-mycarose attached at C-4xe2x80x2) and an acetaldehyde at C-6. 
Considerable research efforts have been carried out on tylosin and its derivatives but not much success has been observed with this subclass. The search for macrolides active against MLSB-resistant strains (MLSB=Macrolides-Lincosamides-Type B Streptogramines) has become a major goal, in addition to improving the overall profile of the macrolides in terms of acid stability, tolerance and pharmacokinetics.
The present invention provides a novel class of 5-O-mycaminosyltylonide (OMT) analogs possessing increased antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives. In addition, the present invention provides a class of 5-O-mycaminosyltylonide analogs that are more acid stable and overcome bacterial resistance.
In one embodiment, the present invention provides compounds represented by Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
In Formula I
A is selected from the group consisting of:
(1) xe2x80x94CHO or a protected aldehyde;
(2) xe2x80x94CN;
(3) xe2x80x94CHxe2x95x90Nxe2x80x94NR6R7, wherein R6 and R7 are each independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
(c) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
(d) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic; and
(e) R6 and R7, taken together with the nitrogen atom to which they are connected, form a 3- to 7-membered ring which may optionally contain a hetero-function selected from the group consisting of: xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(C1-C6-alkyl)-, xe2x80x94N(aryl)-, xe2x80x94N(heteroaryl)-, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, and xe2x80x94S(O)2xe2x80x94;
(4) xe2x80x94CHxe2x95x90Nxe2x80x94OR6, where R6 is as previously defined;
(5) xe2x80x94CH2X, wherein X is selected from the group consisting of:
(a) hydroxy or protected hydroxy;
(b) halogen;
(c) xe2x80x94NR6R7, where R6 and R7 are as previously defined;
(d) xe2x80x94NR6C(O)xe2x80x94R8, where R6 is as previously defined and R8 is selected from the group consisting of:
i. hydrogen;
ii. C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
iii. C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
iv. C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
v. aryl;
vi. substituted aryl;
vii. heterocyclic; and
viii. substituted heterocyclic;
(e) xe2x80x94NR6C(O)xe2x80x94NR7R8, where R6, R7, and R8 are as previously defined;
(f) xe2x80x94NR6xe2x80x94NR7R8, where R6, R7 and R8 are as previously defined;
(g) xe2x80x94NR6xe2x80x94NR7C(O)xe2x80x94R8, where R6, R7 and R8 are as previously described;
(h) xe2x80x94S(O)nxe2x80x94R9, where R9 is selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where n is 0, 1 or 2;
(i) xe2x80x94S(O)nxe2x80x94(C1-C6-alkyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where n is as previously defined;
(j) xe2x80x94S(O)nxe2x80x94(C2-C6-alkenyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where n is as previously defined;
(k) xe2x80x94S(O)nxe2x80x94(C2-C6-alkynyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where n is as previously defined; and
(l) xe2x80x94Oxe2x80x94Mxe2x80x94Y, where M is:
i. absent,
ii. xe2x80x94C(O)xe2x80x94,
iii. xe2x80x94C(O)N(R6)xe2x80x94, where R6 is as previously defined,
iv. C1-C6-alkyl-N(R6)xe2x80x94, where R6 is as previously defined,
v. C2-C6-alkenyl-N(R6)xe2x80x94, where R6 is as previously defined, or
vi. C2-C6-alkynyl-N(R6)xe2x80x94, where R6 is as previously defined,
and where Y is:
i. hydrogen,
ii. C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, xe2x80x94OR6, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where R6 is as previously defined,
iii. C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, xe2x80x94OR6, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where R6 is as previously defined,
iv. C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, xe2x80x94OR6, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where R6 is as previously defined,
v. aryl,
vi. substituted aryl,
vii. heterocyclic, or
viii. substituted heterocyclic;
(6) heterocyclic or substituted heterocyclic;
R1 and R2 are each independently selected from the group consisting of:
(1) hydrogen;
(2) hydroxy;
(3) protected hydroxy;
(4) xe2x80x94OC(O)xe2x80x94C1-C12-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, xe2x80x94OR6, and xe2x80x94NR6R7, where R6 and R7 are as previously defined;
(5) xe2x80x94OR6, where R6 is as previously defined;
(6) halogen;
(7) xe2x80x94NR6R7, where R6 and R7 are as previously defined; and
(8) R1 and R2 taken together are=O;
R3 is selected from the group consisting of:
(1) hydrogen;
(2) a hydroxy protecting group;
(3) xe2x80x94C(O)xe2x80x94C1-C12-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, xe2x80x94OR6, and xe2x80x94NR6R7, where R6 and R7 are as previously defined;
(4) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, xe2x80x94OR6, and xe2x80x94NR6R7, where R6 and R7 are as previously defined;
(5) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, xe2x80x94OR6, and xe2x80x94NR6R7, where R6 and R7 are as previously defined; and
(6) C2-C6-alkynyl, optionally substituted with one or more substitutents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, xe2x80x94OR6, and xe2x80x94NR6R7, where R6 and R7 are as previously defined;
R4 is xe2x80x94Mxe2x80x94Y, where M and Y are as previously defined;
R5 is xe2x80x94Mxe2x80x94Y, where M and Y are as previously defined; and
Rp is hydrogen or a hydroxy protecting group.
In another embodiment, the present invention provides a process for preparing novel compounds represented by Formula I wherein the groups A, R1, R2, R3, R4, R5 and Rp are as previously defined.